This project will define the significance of secretory phospholipases A2 (sPLA2s) in neuronal signaling and injury. Two major goals of this project are to: 1) define how lipid messengers generated by sPLA2s modulate neuronal survival and function, and 2) to identify gene expression in the brain, modulated by sPLA2(s). We have shown that sPLA2s alter neuronal survival and function in vitro and in vivo. We have demonstrated effects of sPLA2s on neuronal calcium homeostasis and cell injury stimulated by glutamate. It is our hypothesis that lipids generated by sPLA2 enzyme activity, such as arachidonic acid and platelet-activating factor, may modulate neuronal excitation at the synapse, and thus alter physiological and pathological outcomes in the brain. Here we will correlate effects at the cellular level with in vivo outcomes such as learning and memory, as well as cell injury in the brain. Arachidonic acid and PAF will be used directly, as well as purified sPLA2s, to modulate neuronal function. A second goal of this project is to identify alterations in gene expression caused by sPLA2s in the brain. This goal will be accomplished by utilizing the DNA Array Core Module. Primary cultures of neurons and astrocytes will be ideal for this technology, as cultures under injury and stress conditions can be compared to determine which genes are upregulated. Brain tissue from experimental animals treated with sPLA2s, PAF, or arachidonic acid will also be used. Thus, the goal of determining the role of endogenous sPLA2 in neuronal function and injury will benefit from the DNA Array Core Module.